Gonadal steroids are major neuroregulators and presumably underlie gender-related differences (sexual dimorphisms) in brain structure and function. We have studied reproductive endocrine-related mood disorders as well as developed endocrine models for these disorders in order to characterize the role of gonadal steroids in affective disturbance. Our major recent findings are as follows: 1) Demonstration of significant differences in the allele and genotype frequencies of the 5HTTLPR polymorphism in women with PMS (93) compared with controls (261); 2) Failure to replicate with CRH in women the luteal phase enhancement of stimulated pituitary-adrenal axis function seen with exercise; 3) Preliminary demonstration that continous administration of combined estradiol and progesterone eliminates premenstrual syndrome after the first stimulated episode (three of four subjects); 4) Failure to demonstrate, in preliminary data, reported menstrual cycle variation in the neurosteroid synthetic enzyme, 3-alpha hydroxysteroid oxido-reductase; 5) Preliminary demonstration that women with PMS differ from controls in progesterone metabolism, with increased levels of DHP and allopregnanolone relative to progesterone seen in patients; 6) Demonstration that patients with PMS differ from those with recurrent brief depression and controls in the standard deviation of prospectively obtained mood ratings but not in the depgree of approximate entropy (ApEn) manifested; 7) Demonstration that women with PMS, in contrast to controls, show strong menstrual cycle phase effects on discrimination of expressed emotion in faces, with more negative judgments seen in the luteal phase. These observations extend known differences between women with PMS and normal women in a manner that may help elucidate the pathophysiology of the differential sensitivity to gonadal steroids seen in this disorder. Additionally, the data with continous hormone administration may not only inform our understanding of the relevant hormonal stimuli that precipitate PMS, but as well may suggest a new therapeutic strategy for the millions of women who suffer from this disorder.